Overall goals: My laboratory is dedicated to understanding and mitigating the neuroinflammatory response to implanted devices within the central nervous system. Such devices range from ventricular shunts to various types of stimulating and recording electrodes. Neural devices range in material type, size, architecture, function, and placement. Regardless of any of these variables, the neuroinflammatory response to the implant plays a significant role on the integrity of the healthy tissue and the longevity of device performance. A progressive decline in recordings quality after implantation has been known for over 40 years. Unfortunately, recording instability is still a commonly documented problem. A major portion of my work has focused on studying various aspects of intracortical microelectrode performance, and pursuing both materials-based and therapeutic-based methods to mitigate the inflammatory-mediated intracortical microelectrode failure mechanisms. Areas include: 1) Role of tissue/device mechanical mismatch on microelectrode failure. I have developed biologically- inspired, mechanically-dynamic intracortical microelectrodes based on their polymer nanocomposite material. Enabled by the novel material system, I am able to independently examine and manipulate device modulus, geometry, and drug-eluting capabilities. Over the past ten years, my team has successfully demonstrated that mechanically-dynamic polymer-based intracortical microelectrodes are stiff enough to be inserted into the brain, become compliant to reduce micro-motion and inhibit late-stage neuroinflammatory responses, and can be fabricated into functional intracortical microelectrodes capable of recording from neural structures in live animals. We have also recently demonstrated that mechanically-dynamic polymer-based intracortical microelectrodes can be utilized to deliver anti-inflammatory therapeutics to further mitigate implant-associated inflammation. As part of our ongoing Department of Defense CDMRP award, we are collaboratively working to characterize the relationship between microelectrode-induced tissue strain and recording performance. 2) Role of oxidative stress on microelectrode failure. Oxidative pathways have been implicated in both neurodegeneration and corrosive damage to both the metallic and insulating materials of current intracortical microelectrode technologies. Thus, approaches to mitigate or attenuate the deleterious effects of oxidative inflammatory products are of significant importance. We have demonstrated that several antioxidants can be delivered systemically or locally to temporally mitigate neuronal damage and loss, and that bioactive coatings with mimetic anti-oxidative enzymes can prolong neuroprotection. Further, unpublished results have also established a correlation between osmotically delivered antioxidant therapy within the brain and improved intracortical microelectrode recording performance. Over the next four years, my new VA Merit Review will explore the connection between surface-immobilize biomimetic antioxidative therapies and intracortical microelectrode recording performance. 3) Role of specific immunity pathways microelectrode failure. Few direct connections have been demonstrated between the neuroinflammatory response to intracortical microelectrodes and device performance. We have identified a possible connection between each of these studies to be in large part due to innate immunity-specific toll-like receptor pathways of resident microglia or infiltrating macrophages. Further, we have established that inhibiting the innate immunity co-receptor cluster of differentiation 14 on myeloid cells and not resident microglia reduced blood-brain barrier permeability and increased neuroprotection and intracortical microelectrode recording performance. My laboratory has identified a precise pathway that facilitates stability of the microelectrode-tissue interface, which may lead to new treatment regimens to enable long-term performance. Ongoing work is supported by the NIH, with interest from private corporate sources.